title: Angiotensin II receptor blocker attenuates intrarenal renin-angiotensin-system and podocyte injury in rats with myocardial infarction.
abstract: The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS)-induced podocyte injury. Sprague-Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16(ink4a), decreased immunostaining for Wilms' tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2'-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16(ink4a)-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.
authors.affiliation: Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhu-zhi
authors.initials: ZZ
authors.lastname: Wen
authors.forename: Mu-yan
authors.initials: MY
authors.lastname: Cai
authors.forename: Zun
authors.initials: Z
authors.lastname: Mai
authors.forename: Dong-mei
authors.initials: DM
authors.lastname: Jin
authors.forename: Yang-xin
authors.initials: YX
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Deng-feng
authors.initials: DF
authors.lastname: Geng
authors.forename: Jing-feng
authors.initials: JF
authors.lastname: Wang
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016922:Cellular Senescence; D015870:Gene Expression / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy*; D018384:Oxidative Stress; D050199:Podocytes / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000209:etiology / Q000517:prevention & control*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D019808:Losartan